The aim of the present study was to evaluate
p38 MAPK activation following focal
stroke and determine whether
SB 239063, a novel second generation p38 inhibitor, would directly attenuate early neuronal injury. Following permanent
middle cerebral artery occlusion (MCAO), brains were dissected into ischemic and non-ischemic cortices and Western blots were employed to measure
p38 MAPK activation.
Neurologic deficit and MR imaging were utilized at various time points following MCAO to monitor the development and resolution of
brain injury. Following MCAO, there was an early (15 min) activation of
p38 MAPK (2.3-fold) which remained elevated up to 1 h (1.8-fold) post injury compared to non-ischemic and
sham operated tissue. Oral
SB 239063 (5, 15, 30, 60 mg/kg) administered to each animal 1 h pre- and 6 h post MCAO provided significant (P<0.05) dose-related neuroprotection reducing
infarct size by 42, 48, 29 and 14%, respectively. The most effective dose (15 mg/kg) was further evaluated in detail and
SB 239063 significantly (P<0.05) reduced
neurologic deficit and
infarct size by at least 30% from 24 h through at least 1 week. Early (i.e. observed within 2 h) reductions in diffusion weighted imaging (DWI) intensity following treatment with
SB 239063 correlated (r=0.74, P<0.01) to neuroprotection seen up to 7 days post
stroke. Since increased
protein levels for various pro-inflammatory
cytokines cannot be detected prior to 2 h in this
stroke model, the early improvements due to p38 inhibition, observed using DWI, demonstrate that p38 inhibition can be neuroprotective through direct effects on ischemic brain cells, in addition to effects on
inflammation.